DD289526A5 - NEW CHEMICAL PROCESSES - Google Patents

Abstract

A process is described for the preparation of alkali metal salts of tetrazole-5-carboxylic acid, which comprises reacting an alkali metal azide in a reaction medium of a tertiary amine as the base and a strong acid with a cyanoformic acid alkyl ester and without purification of the tetrazole-5 product thus prepared. followed by carboxylic acid ester reaction in situ with an alkali metal hydroxide. The alkali metal salt of tetrazole-5-carboxylic acid thus obtained can be used for the preparation of pharmaceuticals. {Alkali metal salt-tetrazole-5-carboxylic acid preparation; Reaction alkali metal azide with alkyl cyanoformate; Reaction medium-amine tertiary acid, strong; Reaction of alkali metal hydroxide; pharmaceuticals}

Description

Field of application of the invention

This invention relates to a novel process for the preparation of salts of tetrazole-5-carboxylic acid and their use in the manufacture of pharmaceuticals.

Characteristic of the known state of the art

In GB Patent No. 2,006,782B and in the specifications of the related patents and patent applications filed outside the UK, e.g. No. 4,442,115, inter alia, a process for the preparation of compounds of the general formula as shown in Figure 1 of the drawings, which are summarized at the end of this specification [wherein R ^{1 is} a straight or branched Alkylsulfonyl or alkylsulfamoyl group, each containing from 1 to 6 carbon atoms, a dialkylsulfamoyl or dialkylcarbamoyl group (wherein the two alkyl groups may be the same or different and each containing from 1 to 4 carbon atoms), a straight-chain or branched alkanoyl, alkoxycarbonyl or alkylcarbamoyl group having 3 to 8 carbon atoms in the cycloalkyl moiety, or a formyl, trifluoroacetyl, sulfamoyl, cyano, carbamoyl, aralkanoyl (e.g., a phenylacetyl) or aroyl group (e.g., a benzoyl group) R ^{2 is} a halogen atom or a straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, each of which is 1 a straight chain or branched alkanoyl, alkoxycarbonyl, alkoxycarbonylamino, alkylcarbamoyl or alkanoylamino group having 2 to 6 carbon atoms, a cycloalkylcarbonyl group having 3 to 8 carbon atoms in the cycloalkyl moiety, or a formyl, nitro, trifluoromethyl, trifluoroacetyl, aryl (ζ. Phenyl), benzyloxycarbonylamino, sulfamoyl, tetrazol-5-yl, carbamoyl, benzyloxy, aralkanoyl (e.g., phenylacetyl), or aroyl (e.g., benzoyl) or a group of the formula

-CR ³ = NOR ⁴ (II)

(wherein R ^{3 represents} a hydrogen atom or a straight-chain or branched alkyl group having 1 to 5 carbon atoms, an aryl (eg phenyl), aralkyl (eg benzyl) or trifluoromethyl group or a cycloalkyl group having 3 to 8 carbon atoms and R ^{4 is} a hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms optionally substituted by a phenyl group or an aryl group (eg a phenyl group) optionally substituted by one or more substituents such as halogen atoms, straight or branched alkyl and Alkoxy groups having 1 to 6 carbon atoms, hydroxyl, trifluoromethyl or nitro groups is substituted) and η is 0 or the integer 1 or 2 and the substituents R ^{2 may be the} same or different, when n2 represents] by reacting a A compound of the general formula shown in Figure III (wherein R ¹ , R ² and η are as defined hereinbefore), with the dipotassium salt of the tetrazole-5-carboxylic acid in the presence of N, N-dimethyl- (chloromethylimmonium) chloride or a source thereof (e.g. A mixture of dimethylformamide and an acid chloride such as oxalyl chloride) preferably near or below room temperature, e.g. Between -25 ° C. and + 35 ° C. The compounds of the formula as shown in Figure I have valuable pharmacological properties, in particular valuable properties in the treatment of allergic conditions, for example of Respiratory disorders, such as those manifested in the interaction of tissue-fixed antibodies with specific antigens, for example allergic bronchial asthma.

In the above-mentioned patent specifications, the preparation of the dipotassium salt of tetrazole-5-carboxylic acid is described as follows, using ethyl cyanoformate and an azide such as sodium azide, trimethylsilyl azide or tributyltin azide as starting materials, and isolating the tetrazole-5-carboxylic acid ethyl ester as an intermediate Dipotassium salt is produced therefrom by reaction with potassium hydroxide

 Tetrazole-5-carboxylic acid ethyl ester was prepared by the following procedures:

(a) 2, g of ethyl Cyanoformate were dissolved in 10 ml of dry pyridine and to this solution was added, while stirring, a cooled mixture of 4.4 ml of trifluoroacetic acid and 15 ml of dried pyridine. The suspension was admixed with 1.8 g of Nairiumazid with stirring and the resulting mixture for 48 hours at 60-65 ° C stirred. The mixture was then cooled to room temperature and poured onto 100 g of a mixture of ice and concentrated hydrochloric acid. The mixture was then extracted with 3x 30ml diethyl ether and dried the combined ether extracts over magnesium sulfate and evaporated to dryness to give an oil [which in the slurry with petroleum ether, boiling point = 40-6O ⁰ C, partially crystallized] which was purified by chromatography on silica was eluting with a mixture (1: 1, by volume) in petroleum ether, bp 40-60 ⁰ C, and diethyl ether was eluted to give tetrazole-5-carboxylic acid ethyl ester was obtained, m.p. = 88-93 "C, yield 1 , 57 g = 45%, based on the ethyl chloroformate.

(b) When performing serve in the same way reaction, but replacing the pyridine to the corresponding amount of 2,6-Dimevhylpyridin, is tetrazol-5-carboxylic acid ethyl ester, m.p. = 80-92 ⁰ C, Yield = 35% , based on the ethyl chloroformate.

(c) A solution of 0.58 g of trimethylsilyl azide and 0.5 g of cyanoformate in 20 ml of dried benzene are refluxed for 48 hours. This solution was then allowed to stand at room temperature for 4 days and the resulting white solid filtered off to give tetrazole-5-carboxylic acid ethyl ester, F = 88-93 ° C, yield 0.3g = 37% based on the ethyl chloroformate has been.

(d) Substituting in the same manner as above but replacing the benzene with an appropriate amount of ethyl acetate, ethyl tetrazole-5-carboxylate, F = 86-9O ⁰ C, yield 0.5g = 61%, based on ethyl chloroformate.

(o) A solution of 6.65 g of tributyltin azide and 1.98 g of ethyl cyanoformate in 25 ml of dry benzene was refluxed for 48 hours. The benzene was distilled off under reduced pressure and the residue was dissolved in an excess solution of hydrogen chloride in ethanol. This mixture was allowed to stand and then the ethanol was removed in vacuo on a rotary evaporator to give a red oil.

Chromatography of this oil over a silica gel eluting with a mixture of methanol and chloroform (1: 9, v / v) afforded tetrazole-5-carboxylic acid ethyl ester identical to samples prepared by the other methods as described described above. The dipotassium salt of tetrazole-5-carboxylic acid was prepared as follows:

0.36 g of tetrazole-B-carboxylic acid ethyl ester were dissolved in 7.5 ml of hot ethanol and to this solution with a solution of 0.22 g of potassium hydroxide in 0.7 ml of water. The white solid thereby obtained was filtered off and washed with ethanol to give the dipotassium salt of tetrazole-5-carboxylic acid was obtained which did not melt below 330 ⁰ C (yield 0.16 g = 33% based on tetrazol-ö-carboxylic acid ethyl ester) ,

In these examples, the total yield of the dipotassium salt of tetrazole-5-carboxylic acid, based on ethyl chloroformate, is between δ 3% x 35% = 12% and 33% χ 61% = 20%.

Object of the invention

The present invention provides a simpler process of higher yields and greater safety for the preparation of alkali metal salts of tetrazole-5-carboxylic acid, wherein the tetrazole-5-carboxylic acid ester is not isolated.

Explanation of the essence of the invention

The invention has for its object to find a method for the preparation of alkali metal salts of tetrazole-5-carboxylic acid, which allows better results than the known.

According to the invention, a process for the preparation of alkali metal salts of the tetrazole-5-carboxylic acid of the general formula IV (see formula sheet p. 15, Fig. IV) is provided.

Another object of the invention is that gett Nden was that other alkali metal salts of tetrazole-5-carboxylic acid. For example, the disodium salt can be used to replace the dipotassium salt of the tetrazole-5-carboxylic acid in the reaction with compounds of the formula shown in Figure III to give compounds of the formula as shown in Figure I are shown prepared. The addition of the dipotassium salt of tetrazole-5-carboxylic acid hitherto unknown alkali metal salts of tetrazole-5-carboxylic acid represent a further subject of this invention.

Another object of this invention is formed by the alkali metal salts of tetrazole-5-carboxylic acid when prepared by the improved process of the present invention.

Accordingly, this invention provides a process for the preparation of an alkali metal salt of the tetrazole-5-carboxylic acid of the general formula as shown in Figure (IV) (wherein M represents an alkali metal atom, preferably a potassium or sodium atom) which consists of reacting an alkali metal azide, e.g. For example, sodium azide, in a medium of anhydrous tertiary amine containing a strong acid with a cyanoformate, preferably having 1 to 4 carbon atoms in the alkyl group, reacting and then without isolation of tetrazole-5-carboxylic acid ester thus prepared by reaction with an alkali metal hydroxide of the formula

MOH (V)

wherein M is as hereinbefore defined, to prepare in situ the alkali metal salt of the tetrazole-5-carboxylic acid. In general, the cyanoformate after the alkali metal azide is added to the reaction mixture.

The tertiary amine used as the base is generally an alkylpyridine or a dialkylpyridine (wherein the alkyl groups in these compounds preferably contain from 1 to 4 carbon atoms and are preferably methyl groups) or, preferably, pyridine. The strong acid is, for example, p-toluenesulfonic acid or, preferably, trifluoroacetic acid. The reaction of the alkali metal azide with the cyanoformic acid alkyl ester is usually carried out at temperatures between 15 ° C and 8O ⁰ C and thereafter is preferably a treatment with an alkanol (which preferably has 1 to 4 carbon atoms and, for example, is ethanol) and a aqueous solution of an alkali metal hydroxide or with an aqueous-alcoholic solution of the alkali metal hydroxide at 50 to 80 ° C, preferably at 60 to 65 ° C, carried out. Thereafter, the reaction mixture is preferably cooled to 0 ⁰ C to 20 ° C and the precipitated salt of the formula, as shown in Figure IV, then isolated, for. B. by filtration. The alkali metal ion in the alkali metal azide is preferably the same alkali metal as that in the desired product.

The strong acid preferably has the following characteristics:

(i) it should be a sufficiently strong acid capable of forming the alkali metal azide

To release hydrazoic acid; and (ii) said acid should form pyridinium salts (or, when the corresponding compound has been used, the alkylpyridinium or dialkylpyridinium salts) sufficiently in pyridine (or in the alkylpyridine or dialkylpyridine, the

as an alternative reaction medium) are soluble. p-To! sulfonic acid and especially trifluoroacetic meet these requirements.

By applying this new method, and in particular by using the preferred process conditions described above, one or more of the following advantages can be guaranteed:

1. The yields of the new process are very high or even almost quantitative and are therefore much higher than the achievable yields by the previously known methods.

2. According to the methods used hitherto [variants (a) and (b)], it was necessary to separate the tetrazole-5-carboxylic acid ethyl ester from the trifluoroacetic acid, which was difficult because both compounds have a very similar acid strength. According to the new method, the dialkali metal salts of tetrazole-5-carboxylic acid obtained as products are readily separated from the alkali metal trifluoroacetate or p-toluenesulfonate, since these are present in the reaction mixture and in

Solvents such as ethanol, which can be used to wash the filtered precipitates of the dialkali metal salts of tetrazole-5-carboric acid, are much more readily soluble. It has been found that the product produced by the new process does not contain substantial amounts of alkali metal trifluoroacetate or alkali metal p-toluenesulfonate as impurities.

3. In the method used so far [variants (a), (b) and (c) | At the reaction stage of the reaction with acid, hazardous, explosive and highly toxic hydrazoic acid gas was released.

In the production on technical scales, this would have to be removed, for. B. by passing nitrogen through it and the gas mixture thus prepared is removed.

4. The reaction of alkali metal azide and alkyl cyanoformate in the mixture of pyridine and acid is highly exothermic, however, according to the new process, the alkyl cyanoformate after the alkali metal azide is added to the reaction mixture and this facilitates control of the reaction temperature.

5. It has been determined by thermal stability studies that the heating of tetrazole-5-carboxylic acid alkyl esters is potentially hazardous and involves the risk of explosions. The new process avoids the potentially hazardous stage in the process used hitherto, namely the evaporation of the solution of a tetrazole-S-carboxylic acid alkyl ester in an organic solvent. It has been shown that the Dialkalimetallsulze of tetrazole-5-carboxylic acid are thermally stable up to temperatures of 300 ⁰ C (the upper limit of the experimental apparatus).

6. The new process does not require the expensive steps of chromatography or extraction with solvents such as diethyl ether.

7. If an alkali metal ion other than the alkali metal M in the desired product is selected in the alkali metal azide, little contamination of the product by the salt of the alkali metal may occur from the azide. This problem can be overcome by using the same alkali metal in the azide and hydroxide of formula (V). For economic reasons, the sodium compounds are usually chosen for production on an industrial scale.

This invention also provides a process for the preparation of compounds shown in Figure I, in particular compounds shown in Figure I and in which R 'is a straight or branched alkanoyl group of 2 to 6 carbon atoms, e.g. An acetyl group, and (R ² I _{n is} optionally a substituent in the para position of the ring with respect to the indicated hydroxyl groups, for example, a halogen atom or a cyano group or a straight-chain or branched alkyl group having 1 to 6, preferably 1 to 3 carbon atoms, eg

S'-acetyl ^ '- hydroxy-tetrazol-ö-carboxanilide

S'-acetyl-ö'-cyano ^ '- hydroxy-tetrazol-ö-carboxanilide

S'-acetyl ^ '- hydroxy-ö'-methyl-tetrazol-S-carboxanilide

S'-acetyl-6'-ethyl ^ '- hydroxy-tetrazole-6-carboxanilide or in particular

S'-acetyl-ö'-fluoro ^ '- hydroxy-tetrazol-ö-carboxanilide

which method is to prepare an alkali metal salt of tetrazole-5-carboxylic acid prepared by the process of the present invention with a compound of the general formula shown in Figure (III) wherein R ', R ² and η have the meaning already defined herein, in the presence of NfN-dimethyl chloromethylenepolymium chloride or a source thereof.

The following examples illustrate the invention:

embodiments

example 1

A slurry of 18.0 g of sodium azide in 200 ml of dry pyridine was added with stirring at 15 ⁰ C with 34.7 g of trifluoroacetic acid. To this mixture 25.0 g Cyanameisensäure ethyl ester were added and then stirred at 65 ° C for another 48 hours at 65 ⁰ C. Subsequently, the mixture was cooled to 60 ° C and 150 ml of ethanol was added. Thereafter, a solution of 35.0 g of potassium hydroxide in 35 ml of water was added. The mixture was then stirred at 65 ⁰ C for 15 minutes, the mixture was cooled to room temperature and filtered, whereby 42.5g of the dipotassium salt of tetrazole-5-carboxylic acid (yield 89.4%, based on the cyanoformic acid ethyl ester) in the form of a white, crystalline Solid were obtained.

Example 2

A slurry of 62.8 g of sodium azide in 800 ml of dry pyridine was added at 15 ° C with stirring with 121.6 g of trifluoroacetic acid and then with 100 g of ethyl cyanoformate. This mixture was stirred for 6 hours at 70-75 ⁰ C, then cooled to 60 ⁰ C and treated with 600 ml of ethanol. Subsequently, a solution of 88 g of sodium hydroxide in 120 ml of water was added.

The mixture was then stirred for 15 minutes at 65 ⁰ C, the mixture was cooled to room temperature and filtered, whereby 157.7g of the disodium salt of tetrazole-5-carboxylic acid (yield 99.8%, based on the cyanoformic acid ethyl ester) in the form of a white, crystalline Solid were obtained.

Example 3

A slurry of 90 g of disodium salt of tetrazole-5-carboxylic acid in 570 ml of dimethylformamide was added over 30 minutes at -2O ⁰ C with 78g thionyl chloride, and this mixture was stirred at -2O ⁰ C for a further hour.

Within 30 minutes, a solution of 96 g of 3-amino

5-Fluoro-2-hydroxy-acetophenone in a mixture of 240 ml of dimethylformamide and 190 ml of pyridine, keeping the temperature at -20 ° C. Thereafter, the mixture was warmed to room temperature and then stirred at 9O ⁰ C for one hour. The resulting mixture was cooled to 2O ⁰ C, diluted with 2900 ml of water, by adding

concentrated hydrochloric acid, acidified to pH 1 and filtered to give 110g 3'-acetyl-5'-fluoro-2'-hydroxy-tetrazol-5-carboxanilide, m.p. = 230-231 ⁰ C (with decomposition) (yield: 72 , 5%). Recrystallization from glacial acetic acid were 95g purified 3'-acetyl-5'-fluoro-2'-hydroxy-tetrazol-5-carboxanilide, F = 232-233 ⁰ C obtained. The same results were obtained when the disodium salt of tetrazole-5-carboxylic acid used as starting material was replaced by the corresponding amount of the dipotassium salt of tetrazole-5-carboxylic acid,

OH

NHCO.

Tl \

1IH

FIG. I

OH

(H ² )

, NH,

FIG. Ill

0OC.

FIG. IV

Claims (15)

1. A process for the preparation of alkali metal salts of tetrazole-5-carboxylic acid of the general formula "OOC-J ₁ - fi u + (IV), Ji I < N Λ wherein M represents an alkali metal atom, characterized in that an alkali metal azide is reacted in a reaction medium of anhydrous tertiary amine as a base and a strong acid with a cyanoformic acid alkyl ester and then without isolation of the thus prepared tetrazole-5-carboxylic acid G-alkyl ester of these in situ with an alkali metal hydroxide of the formula MOH (V), wherein M has the meaning as already stated, is reacted, whereby the alkali metal salt of tetrazole-5-carboxylic acid is prepared. 2. The method according to claim 1, characterized in that the tertiary amine used as the base is pyridine, an alkylpyridine or a dialkylpyridine. 3. The method according to claim 1 or 2, characterized in that the strong acid is p-toluenesulfonic acid. 4. The method according to claim 1 or 2, characterized in that the strong acid is trifluoroacetic acid. 5. The method according to any one of the preceding claims, characterized in that the reaction of the alkali metal azide and the alkyl cyanoformate is carried out at a temperature between 15 ⁰ C and 80 ⁰ C. 6. The method according to any one of the preceding claims, characterized in that the alkali metal azide is sodium azide. 7. ancestors according to any one of the preceding claims, characterized in that the cyanoformic acid alkyl ester is cyanoformate. 8. The method according to any one of the preceding claims, characterized in that the tetrazole-5-carboxylic acid alkyl ester is reacted with an alcohol and an aqueous solution of an alkali metal hydroxides or with an aqueous-alkanolic solution of an alkali metal hydroxide at a temperature between 50 and 8O ⁰ C. , 9. The method according to claim 8, characterized in that the temperature is between 60 and 65 ° C. 10. The method according to any one of the preceding claims, characterized in that after the reaction of the tetrazole-5-carboxylic acid alkyl ester with the alkali metal hydroxide, the reaction mixture is cooled to 0 ⁰ C to 20 ⁰ C to precipitate the alkali metal salt of tetrazole-5-carboxylic acid , 11. The method according to any one of the preceding claims, characterized in that subsequently the alkali metal salt of tetrazole-5-carboxylic acid thus obtained with a compound of general formula (HD, H wherein R ^{1 is} a straight-chain or branched alkylsulfonyl or alkylsulfamoyl group, each of which may have 1 to 6 carbon atoms, a dialkylsulfamoyl or dialkylcarbamoyl group (wherein the two alkyl groups are the same or different from each other and each may have 1 to 4 carbon atoms), a straight-chain or branched alkanoyl, alkoxycarbonyl or alkylcarbamoyl group having 2 to 6 carbon atoms, a cycloalkylcarbonyl group having 3 to 8 carbon atoms in the cycloalkyl radical or a formyl, trifluoroacetyl, sulfamoyl, cyano, Carbo-lyto-.Aralkanoyl or aroyl group, R ^{2 is} a halogen atom or a straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, each of which groups may have 1 to 6 carbon atoms, a dialkylsulfamoyl, dialkylamino or dialkylcarbamoyl group (wherein the two alkyl groups may be the same or different and each having from 1 to 4 carbon atoms), a straight-chain or branched alkanoyl, alkoxycarbonyl, alkoxycarbonylamino, alkylcarbamoyl or alkanoyiamino group having 2 to 6 carbon atoms, a cycloalkylcarbonyl group having 3 to 8 carbon atoms in the cycloalkyl radical, or a formyl, Ni trifluoromethyl, aryl, benzyloxycarbonylamino, sulfamoyl, cyano, tetrazol-5-yl ·, carbamoyl, benzyloxy, aralkanoyl or aroyl group or a group of the formula -CR ³ = NOR ⁴ (II), (wherein R ^{3 is} a hydrogen atom or a straight-chain or branched alkyl group having 1 to 5 carbon atoms, an aryl, aralkyl or trifluoromethyl group or a cycloalkyl group having 3 to 8 carbon atoms and R ^{4 is} a hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms optionally substituted by a phenyl group or an aryl group optionally substituted by one or more substituents such as halogen atoms, straight or branched alkyl or alkoxy groups having from 1 to 6 carbon atoms, hydroxyl, trifluoromethyl or nitro groups), and η is zero or one whole Number 1 or 2, wherein the substituents R ^{2 may be the} same or different from each other, when η 2, in the presence of N, N-dimethyl (chloromethylenemethonium) chloride or a source thereof as a compound of the general formula OH wherein R ¹ , R ² and η are as hereinbefore defined. 12. The method according to claim 11, characterized in that R ^{1 represents} a straight-chain or branched alkanoyl group having 2 to 6 carbon atoms and (R ² ) _{n represents} a possibly present substituent in the para position of the ring with respect to the indicated hydroxyl group. 13. The method according to claim 11 or 12, characterized in that R ^{1 represents} an acetyl group and the possibly present substituent is a halogen atom or a cyano group or a straight-chain or branched alkyl group having 1 to 6 carbon atoms. 14. The method according to claim 11,12,13 for the preparation of a compound of general formula (I) as defined in claim 11, characterized in that this compound S'-acetyl ^ '- hydroxy-tetrazole-ö-carboxanilide '3'-Acetyl-5'-cyano-2'-hydroxy-tetrazole-5-carboxynilide, S'-acetyl-1'-hydroxy-B'-methyltetrazole-B-carboxanilide or S'-acetal-B'-ethyl' ' hydroxytetrazole-δ-carboxanilide. 15. The method according to claim 11,12 or 13 for the preparation of a compound of general formula (I) as defined in claim 11, characterized in that this compound 3'-acetyl-5'-fluoro-2'-hydroxy tetrazole-5-carboxanilide. For this 1 page formulas